Twenty-Four-Hour Efficacy of the Brinzolamide 1%/Brimonidine 0.2% Fixed Combination: What Does the New Evidence Tell Us?

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Twenty-four-hour efficacy of the brinzolamide 1%/brimonidine 0.2% fixed combination: what does the new evidence tell us?

Anastasios G. Konstas1,2, Andreas Katsanos3

11st University Department of Ophthalmology, 23rd University Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Ophthalmology Department, University of Ioannina, Ioannina, Greece Correspondence to: Prof. Anastasios G. Konstas. 1st University Department of Ophthalmology, Aristotle University of Thessaloniki, Thessaloniki, Greece. Email: [email protected]. Comment on: Weinreb RN, Bacharach J, Fechtner RD, et al. 24-Hour Intraocular Pressure Control with Fixed-dose Combination Brinzolamide 1%/ Brimonidine 0.2%: A Multicenter, Randomized Trial. Ophthalmology 2018. [Epub ahead of print].

Received: 06 February 2019; Accepted: 28 February 2019; Published: 04 March 2019. doi: 10.21037/aes.2019.02.02 View this article at: http://dx.doi.org/10.21037/aes.2019.02.02

The importance of 24-hour intraocular pressure (IOP) 2 decades (6,7). This is more crucial with available medical assessment has increasingly being recognized in recent years therapy options as most medications lower IOP more (1-4). In cardiology, 24-hour blood pressure monitoring during the day than during the night (5-7). Controlled is widely employed to accurately characterize a patient’s 24-hour efficacy evidence over the years has unveiled blood pressure profile and to guide management. Similarly, the true magnitude of IOP-lowering provided by several in glaucoma care 24-hour IOP assessment can delineate a antiglaucoma medications and directly impacted their patient’s true pressure characteristics and guide stepwise adoption and popularity in clinical practice. For example, a decision-making (1,5). Nevertheless, the precise predictive key reason for the adoption of prostaglandins as first option value of a short-term 24-hour untreated, or treated curve therapy worldwide was their superior 24-hour efficacy (6-7). upon the long-term prognosis of glaucoma remains to be In contrast, the reduced efficacy of timolol and brimonidine elucidated. There is some evidence suggesting that those during the night reduced their appeal in glaucoma patients with fluctuating 24-hour IOP characteristics management. Published 24-hour studies have delineated manifest greater degrees of ocular damage and efficacy results which would have remained unknown if only functional deterioration than those with stable pressures daytime assessment had been performed (9-11). (1,6-8). Consequently, notwithstanding practicality issues, In view of the key role played by 24-hour IOP monitoring untreated 24-hour IOP characteristics can monitoring in the evaluation of a novel antiglaucoma provide important evidence to tailor more precisely target medication, the recently published study by Weinreb pressure requirements and optimize therapy selection. and coworkers (12) is a welcome addition to the existing In treated glaucoma patients, 24-hour IOP monitoring literature. This is especially so because the authors evaluated determines the quality of IOP control and detects a relatively new therapeutic option, the brinzolamide detrimental predictive features such as high peak and 1%/brimonidine 0.2% fixed combination (BBFC), which 24-hour IOP wide fluctuation. This evidence greatly represents the first commercially available beta blocker-free influenced the management of progressive glaucoma antiglaucoma fixed combination. As such, BBFC may prove patients on medical therapy with “apparently good IOP a valuable option for patients in whom topical beta-blockers control” as determined by single IOP measurements in the are contraindicated due to systemic conditions such as clinic (3,4). asthma or bradycardia. Beyond patient management, 24-hour studies have In their study, Weinreb et al. (12) present the results of a enabled researchers to better describe the true 24-hour 4-week, prospective, multicenter, double-masked, placebo- efficacy of many novel therapeutic options over the last controlled trial in 16 academic and non-academic sites in

© Annals of Eye Science. All rights reserved. aes.amegroups.com Ann Eye Sci 2019;4:11 Page 2 of 4 Annals of Eye Science, 2019 the USA. Following an appropriate wash-out period and a masked, placebo-controlled study) is optimal and it should baseline 24-hour IOP curve, 125 subjects with either open- be highlighted that few controlled studies to date have angle glaucoma, or ocular hypertension were randomized included a placebo arm in assessing the efficacy of a therapy 1:1 to either BBFC or placebo, each dosed 3 times daily option. Indeed, to the best of our knowledge this is the for 4 weeks. A treated 24-hour IOP curve was repeated at first 24-hour study, which is placebo-controlled. Finally, the end of the 4-week period with IOP readings performed the present study has been conducted in strictly regulated every 2 hours in the habitual position (sitting IOP between conditions of a sleep laboratory. 08:00 and 20:00 and supine IOP readings between 22:00 and On the other hand, as with all studies there are 06:00). The IOP was evaluated with a pneumotonometer in limitations. First, IOP measurements in several of the 16 overnight facilities with controlled lighting conditions. participating overnight facilities were performed by The authors reported that BBFC significantly reduced mean trained, but inexperienced personnel. Indeed, many of 24-hour IOP compared to placebo [least squares mean the participating sites established their overnight facilities difference (95% confidence interval): −2.5 (−3.3 to −1.7)]. specifically for this study. Secondly, the rigorously Therapy with BBFC reduced mean IOP from baseline by controlled conditions and the IOP and blood pressure 14–22% during the daytime period, and by 6–9% during monitoring every 2 hours may impact the routine circadian the nocturnal period. The frequency of adverse events was activity of some study patients. Inherent problems with all similar between the 2 groups during this 4-week trial. 24-hour monitoring studies are that IOP measurements Consequently, it appears that despite the thrice-daily may be influenced by factors such as the stress of waking, dosage, the overall efficacy of BBFC was modest. Moreover, and the precision of tonometry in low-light conditions. the nocturnal reduction in least squares mean IOP of An important methodological consideration is that by 1.2 mmHg with BBFC vs. placebo did not achieve statistical employing a pneumotonometer to evaluate IOP, the results significance in the full analysis set (12). This is consistent of the present study do not reflect the Goldmann gold to some extent with previous 24-hour evidence showing standard employed in clinical practice and the evidence reduced efficacy of brimonidine at night (11,13,14). It accumulated with Goldmann technology in many other is more surprising though with regard to the second previous 24-hour studies. component of the fixed combination: brinzolamide. A meta- The study by Weinreb et al. (12) represents a significant analysis of 24-hour studies (15) reported that dorzolamide contribution to the available evidence on the 24-hour (a carbonic anhydrase inhibitor just like brinzolamide) efficacy of the recently introduced BBFC (18). Several issues was the only glaucoma medication working better during with regard to BBFC need to be addressed in the future. In the night (21%) than during the day (16%). If carbonic Europe BBFC is mostly prescribed twice daily. It remains to anhydrase inhibitors are the only class of antiglaucoma be seen what the 24-hour efficacy of BBFC is when dosed medications working better during the night than during twice daily. This issue is clinically relevant as it will influence the day (6,7,15) the intriguing question then is why this 24-hour efficacy, long-term tolerability and adherence efficacy was not observed in the study with BBFC? Although (5,19,20). Another question is to what extent BBFC causes this pattern of enhanced night-time efficacy relies on delayed hypersensitivity reactions similar in frequency and dorzolamide studies (no published studies exist as yet with severity to those of brimonidine monotherapy (21). Long- brinzolamide) it should be noted that satisfactory night-time term clinical studies and cumulative clinical experience are efficacy has been previously recorded in 24-hour studies desirable to better understand the safety and tolerability profile with other fixed combinations: the timolol/dorzolamide(16) of this novel combination. Future studies should determine the and timolol/brinzolamide (17) fixed combinations. We can comparative 24-hour efficacy of this medication versus that of only hypothesize that the lower magnitude of 24-hour IOP more established therapy options (22). reduction documented here with BBFC may be due to It should not be overlooked that the real efficacy profile variations in study design, patient selection and relatively of all available anti-glaucoma medications would not have low baseline pressures. been detected without a complete 24-hour IOP evaluation. The study by Weinreb et al. (12) has certain How this evidence reflects upon real life efficacy, popularity methodological strengths. With 123 completed patients it and long-term prognosis remains to be elucidated. is the largest 24-hour study ever performed and obviously Nevertheless, Weinreb and colleagues (12) should be is more than adequately powered. Its design (double- applauded for evaluating the 24-hour efficacy of BBFC

© Annals of Eye Science. All rights reserved. aes.amegroups.com Ann Eye Sci 2019;4:11 Annals of Eye Science, 2019 Page 3 of 4 in a large controlled study and for establishing the true fluctuations in intraocular pressure are an independent IOP-lowering characteristics of this novel fixed combination risk factor in patients with glaucoma. J Glaucoma for the first time, as well as setting the bar for future 2000;9:134-42. investigations of this nature. 3. Barkana Y, Anis S, Liebmann J, et al. Clinical utility of intraocular pressure monitoring outside of normal office hours in patients with glaucoma. Arch Ophthalmol Acknowledgments 2006;124:793-7. Funding: None. 4. Hughes E, Spry P, Diamond J. 24-hour monitoring of intraocular pressure in glaucoma management: a retrospective review. J Glaucoma 2003;12:232-6. Footnote 5. Konstas AG, Kahook MY, Araie M, et al. Diurnal and 24-h Provenance and Peer Review: This article was commissioned Intraocular Pressures in Glaucoma: Monitoring Strategies by the editorial office, Annals of Eye Science. The article did and Impact on Prognosis and Treatment. Adv Ther not undergo external peer review. 2018;35:1775-804. 6. Konstas AG, Quaranta L, Bozkurt B, et al. 24-h Conflicts of Interest: Both authors have completed the Efficacy of Glaucoma Treatment Options. Adv Ther ICMJE uniform disclosure form (available at http://dx.doi. 2016;33:481-517. org/10.21037/aes.2019.02.02). Professor AG Konstas has 7. Konstas AG, Katsanos A, Quaranta L, et al. Twenty-four received research support from Allergan, Bayer Hellas, hour efficacy of glaucoma medications. Prog Brain Res Pharmathen Hellas S.A. and Santen as well as honoraria 2015;221:297-318. from Allergan, Novartis, Santen and had congress expenses 8. Konstas AG, Mantziris DA, Stewart WC. Diurnal covered by Allergan, Bayer Hellas, Santen and Vianex. intraocular pressure in untreated exfoliation and primary Assistant Professor A Katsanos has received honoraria open-angle glaucoma. Arch Ophthalmol 1997;115:182-5. from Allergan, Laboratoires Théa, Novartis, Vianex and 9. Konstas AG, Quaranta L, Katsanos A, et al. Twenty-four had congress expenses covered by Laboratoires Théa and hour efficacy with preservative free tafluprost compared Vianex. with latanoprost in patients with primary open angle glaucoma or ocular hypertension. Br J Ophthalmol Ethical Statement: The authors are accountable for all 2013;97:1510-5. aspects of the work in ensuring that questions related 10. Konstas AG, Mikropoulos DG, Embeslidis TA, et al. to the accuracy or integrity of any part of the work are 24-h Intraocular pressure control with evening-dosed appropriately investigated and resolved. travoprost/timolol, compared with latanoprost/timolol, fixed combinations in exfoliative glaucoma. Eye (Lond) Open Access Statement: This is an Open Access article 2010;24:1606-13. distributed in accordance with the Creative Commons 11. Liu JHK, Medeiros FA, Slight JR, et al. Diurnal and Attribution-NonCommercial-NoDerivs 4.0 International nocturnal effects of brimonidine monotherapy on License (CC BY-NC-ND 4.0), which permits the non- intraocular pressure. Ophthalmology 2010;117:2075-9. commercial replication and distribution of the article with 12. Weinreb RN, Bacharach J, Fechtner RD, et al. 24- the strict proviso that no changes or edits are made and the Hour Intraocular Pressure Control with Fixed-dose original work is properly cited (including links to both the Combination Brinzolamide 1%/Brimonidine 0.2%: A formal publication through the relevant DOI and the license). Multicenter, Randomized Trial. Ophthalmology 2018. See: https://creativecommons.org/licenses/by-nc-nd/4.0/. [Epub ahead of print]. 13. Konstas AG, Stewart WC, Topouzis F, et al. Brimonidine 0.2% given two or three times daily versus timolol maleate References 0.5% in primary open-angle glaucoma. Am J Ophthalmol 1. Quaranta L, Katsanos A, Russo A, et al. 24-hour 2001;131:729-33. intraocular pressure and ocular perfusion pressure in 14. Quaranta L, Gandolfo F, Turano R, et al. Effects of glaucoma. Surv Ophthalmol 2013;58:26-41. topical hypotensive drugs on circadian IOP, blood 2. Asrani S, Zeimer R, Wilensky J, et al. Large diurnal pressure, and calculated diastolic ocular perfusion

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doi: 10.21037/aes.2019.02.02 Cite this article as: Konstas AG, Katsanos A. Twenty-four- hour efficacy of the brinzolamide 1%/brimonidine 0.2% fixed combination: what does the new evidence tell us? Ann Eye Sci 2019;4:11.